Liu CR, Zhang M, Wang MQ, Zhang W, Li J, Shi GZ, Liang FF, Li YP, Huang N. CD161+CD8+ T cells in patients with hepatitis B virus-associated hepatocellular carcinoma. World J Gastrointest Oncol 2026; 18(4): 114547 [DOI: 10.4251/wjgo.v18.i4.114547]
Corresponding Author of This Article
Na Huang, PhD, Biological Diagnosis and Treatment Center, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xincheng District, Xi’an 710004, Shaanxi Province, China. huangna_428@163.com
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Gastroenterology & Hepatology
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Basic Study
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Apr 15, 2026 (publication date) through Apr 11, 2026
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World Journal of Gastrointestinal Oncology
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Liu CR, Zhang M, Wang MQ, Zhang W, Li J, Shi GZ, Liang FF, Li YP, Huang N. CD161+CD8+ T cells in patients with hepatitis B virus-associated hepatocellular carcinoma. World J Gastrointest Oncol 2026; 18(4): 114547 [DOI: 10.4251/wjgo.v18.i4.114547]
World J Gastrointest Oncol. Apr 15, 2026; 18(4): 114547 Published online Apr 15, 2026. doi: 10.4251/wjgo.v18.i4.114547
CD161+CD8+ T cells in patients with hepatitis B virus-associated hepatocellular carcinoma
Chen-Rui Liu, Meng Zhang, Mu-Qi Wang, Wen Zhang, Jin Li, Gao-Zhao Shi, Fan-Fan Liang, Ya-Ping Li, Na Huang
Chen-Rui Liu, Meng Zhang, Mu-Qi Wang, Jin Li, Gao-Zhao Shi, Ya-Ping Li, Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
Wen Zhang, Clinical Laboratory, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
Fan-Fan Liang, Na Huang, Biological Diagnosis and Treatment Center, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
Co-corresponding authors: Ya-Ping Li and Na Huang.
Author contributions: Li YP and Huang N contribute equally to this study as co-corresponding authors; Liu CR conceptualized and outlined the manuscript and performed the statistical analysis; Liu CR, Li YP and Huang N contributed to the writing, editing, illustration, and literature review; Zhang M, Wang MQ, and Zhang W assisted with figure preparation; Zhang M supported the literature review; Li J and Shi GZ participated in the collection and testing of blood samples; Huang N and Liang FF provided funding support for this research.
Supported by the Basic and Clinical Integration Project of Xi’an Jiaotong University, No. YXJLRH2022067; and Shaanxi Provincial Basic Research Program in Natural Sciences, No. 2023-JC-YB-647 and No. 2023-JC-QN-0918.
Institutional review board statement: This study was approved by the Ethics Committee of the Second Affiliated Hospital of Xi’an Jiaotong University (Approval No. 2022110).
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: No additional data are available.
Corresponding author: Na Huang, PhD, Biological Diagnosis and Treatment Center, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xincheng District, Xi’an 710004, Shaanxi Province, China. huangna_428@163.com
Received: September 26, 2025 Revised: December 15, 2025 Accepted: January 26, 2026 Published online: April 15, 2026 Processing time: 195 Days and 1.6 Hours
Abstract
BACKGROUND
CD161 in hepatocellular carcinoma (HCC) research remains very limited, despite recent evidence that has implicated it as an immune checkpoint and a potential immunotherapeutic target in cancers such as glioma and breast cancer.
AIM
To examine the CD161, CD8, and programmed death receptor 1 (PD-1) expression profiles in patients with hepatitis B virus-associated chronic liver disease and HCC and to evaluate the effects of PD-1 inhibitors on the expression of these molecules in the peripheral blood of patients with HCC.
METHODS
The CD161, CD8, and PD-1 expression levels in the peripheral blood of individuals with chronic hepatitis B (CHB), decompensated cirrhosis, or HCC and in liver cancer tissues obtained from the HCC group were analyzed using bioinformatics, flow cytometry, qPCR, and immunohistochemistry.
RESULTS
The proportion of CD161+CD8+ T cells was significantly elevated in the peripheral blood of patients with HCC. This result suggested a potential correlation between T-cell exhaustion and chronic inflammation. The bioinformatics analysis revealed a co-expression relationship between CD161 and PD-1, and we found that PD-1 inhibitors effectively decreased the proportion of PD-1+ cells in the peripheral blood but did not significantly affect the CD161 expression. The CD161 immunohistochemical staining intensity was significantly greater in tumor tissues than in both adjacent nontumorous liver tissues and liver tissues from patients with CHB.
CONCLUSION
CD161+CD8+ T cells are PD-1-independent biomarkers of T-cell exhaustion in patients with HCC, as these cells are present at elevated levels in peripheral blood and exhibit increased tissue expression. PD-1 inhibitors effectively reduce PD-1+ cells, but they fail to modulate CD161 expression. This highlights its distinct regulatory mechanism and potential as a novel therapeutic target.
Core Tip: This study reveals elevated CD161+CD8+ T cells in peripheral blood of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) patients, correlating with disease progression. Programmed death receptor 1 (PD-1) inhibitors reduced PD-1+ subsets but did not alter CD161 expression, indicating CD161 operates independently of PD-1 pathways. Critically, CD161 protein overexpression in HCC tissues—exceeding paracancerous and chronic hepatitis B tissues—identifies it as a key immunosuppressive molecule. These findings position CD161 as a promising standalone immunotherapeutic target for enhancing T-cell function in HBV-HCC, beyond current PD-1 blockade strategies.
